Hereditary deficiencies in complement C5 are associated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions

G. M. Pasinetti, G. Tocco, S. Sakhi, W. D. Musleh, M. G. DeSimoni, P. Mascarucci, S. Schreiber, M. Baudry, C. E. Finch

Research output: Contribution to journalArticle

Abstract

Possible roles of the complement (C) system in the normal and injured brain were explored with inbred mice that carried a frameshift mutation in the C5 gene. A congenic pair was used: the C5-sufficient (C5+) B10.D2/nSnJ strain with the functional allele (Hc1) from the C57BL/10J donor strain was compared with the C5-deficient (C5-) B10.D2/oSnJ with the Hc0 allele from the C5-deficient DBA/2J donor strain. In response to the excitotoxin kainic acid (KA), C5- mice had more hippocampal pyramidal neuron death and greater induction of astrocyte mRNAs (GFAP, apoE, apoJ). In primary astrocyte cultures from unlesioned mice, an inflammatory stimulus (LPS) caused greater production of IL-6 and TNF production in C5- mice. These enhanced responses to KA and LPS suggest that hereditary C5 deficits modify responses to neurodegenerative stimuli of neurons and astrocytes. Moreover, unlesioned C5- mice had smaller input-output slopes for the NMDA component of the EPSP amplitude, but enhanced the Ca+2-dependent AMPA binding. Thus, C5 deficits also modify basal properties of glutamatergic neurotransmission that pertain to synaptic plasticity. These findings are also discussed in relation to roles of the C-system in Alzheimer disease (AD). C5 deficiencies may also be considered in the choice of strains as transgene hosts and for genetic analysis of normal and pathological brain functions. In recent transgenic studies for AD, C5- hosts showed greater neurodegeneration, consistent with the present data. These pleiotropic associations of C5 deficiency indicate roles for the C-system in neurodegeneration, but also in normal neural functions.

Original languageEnglish
Pages (from-to)197-204
Number of pages8
JournalNeurobiology of Disease
Volume3
Issue number3
DOIs
Publication statusPublished - Jun 1996

Fingerprint

Complement C5
Astrocytes
Kainic Acid
Alzheimer Disease
Alleles
Frameshift Mutation
Neuronal Plasticity
Pyramidal Cells
Excitatory Postsynaptic Potentials
Neurotoxins
Brain
Apolipoproteins E
N-Methylaspartate
Transgenes
Synaptic Transmission
Interleukin-6
Neurons
Messenger RNA
Genes

ASJC Scopus subject areas

  • Neurology

Cite this

Hereditary deficiencies in complement C5 are associated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions. / Pasinetti, G. M.; Tocco, G.; Sakhi, S.; Musleh, W. D.; DeSimoni, M. G.; Mascarucci, P.; Schreiber, S.; Baudry, M.; Finch, C. E.

In: Neurobiology of Disease, Vol. 3, No. 3, 06.1996, p. 197-204.

Research output: Contribution to journalArticle

Pasinetti, G. M. ; Tocco, G. ; Sakhi, S. ; Musleh, W. D. ; DeSimoni, M. G. ; Mascarucci, P. ; Schreiber, S. ; Baudry, M. ; Finch, C. E. / Hereditary deficiencies in complement C5 are associated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions. In: Neurobiology of Disease. 1996 ; Vol. 3, No. 3. pp. 197-204.
@article{0880ee43187f40bfaaeaf55d4b94076f,
title = "Hereditary deficiencies in complement C5 are associated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions",
abstract = "Possible roles of the complement (C) system in the normal and injured brain were explored with inbred mice that carried a frameshift mutation in the C5 gene. A congenic pair was used: the C5-sufficient (C5+) B10.D2/nSnJ strain with the functional allele (Hc1) from the C57BL/10J donor strain was compared with the C5-deficient (C5-) B10.D2/oSnJ with the Hc0 allele from the C5-deficient DBA/2J donor strain. In response to the excitotoxin kainic acid (KA), C5- mice had more hippocampal pyramidal neuron death and greater induction of astrocyte mRNAs (GFAP, apoE, apoJ). In primary astrocyte cultures from unlesioned mice, an inflammatory stimulus (LPS) caused greater production of IL-6 and TNF production in C5- mice. These enhanced responses to KA and LPS suggest that hereditary C5 deficits modify responses to neurodegenerative stimuli of neurons and astrocytes. Moreover, unlesioned C5- mice had smaller input-output slopes for the NMDA component of the EPSP amplitude, but enhanced the Ca+2-dependent AMPA binding. Thus, C5 deficits also modify basal properties of glutamatergic neurotransmission that pertain to synaptic plasticity. These findings are also discussed in relation to roles of the C-system in Alzheimer disease (AD). C5 deficiencies may also be considered in the choice of strains as transgene hosts and for genetic analysis of normal and pathological brain functions. In recent transgenic studies for AD, C5- hosts showed greater neurodegeneration, consistent with the present data. These pleiotropic associations of C5 deficiency indicate roles for the C-system in neurodegeneration, but also in normal neural functions.",
author = "Pasinetti, {G. M.} and G. Tocco and S. Sakhi and Musleh, {W. D.} and DeSimoni, {M. G.} and P. Mascarucci and S. Schreiber and M. Baudry and Finch, {C. E.}",
year = "1996",
month = "6",
doi = "10.1006/nbdi.1996.0020",
language = "English",
volume = "3",
pages = "197--204",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Hereditary deficiencies in complement C5 are associated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions

AU - Pasinetti, G. M.

AU - Tocco, G.

AU - Sakhi, S.

AU - Musleh, W. D.

AU - DeSimoni, M. G.

AU - Mascarucci, P.

AU - Schreiber, S.

AU - Baudry, M.

AU - Finch, C. E.

PY - 1996/6

Y1 - 1996/6

N2 - Possible roles of the complement (C) system in the normal and injured brain were explored with inbred mice that carried a frameshift mutation in the C5 gene. A congenic pair was used: the C5-sufficient (C5+) B10.D2/nSnJ strain with the functional allele (Hc1) from the C57BL/10J donor strain was compared with the C5-deficient (C5-) B10.D2/oSnJ with the Hc0 allele from the C5-deficient DBA/2J donor strain. In response to the excitotoxin kainic acid (KA), C5- mice had more hippocampal pyramidal neuron death and greater induction of astrocyte mRNAs (GFAP, apoE, apoJ). In primary astrocyte cultures from unlesioned mice, an inflammatory stimulus (LPS) caused greater production of IL-6 and TNF production in C5- mice. These enhanced responses to KA and LPS suggest that hereditary C5 deficits modify responses to neurodegenerative stimuli of neurons and astrocytes. Moreover, unlesioned C5- mice had smaller input-output slopes for the NMDA component of the EPSP amplitude, but enhanced the Ca+2-dependent AMPA binding. Thus, C5 deficits also modify basal properties of glutamatergic neurotransmission that pertain to synaptic plasticity. These findings are also discussed in relation to roles of the C-system in Alzheimer disease (AD). C5 deficiencies may also be considered in the choice of strains as transgene hosts and for genetic analysis of normal and pathological brain functions. In recent transgenic studies for AD, C5- hosts showed greater neurodegeneration, consistent with the present data. These pleiotropic associations of C5 deficiency indicate roles for the C-system in neurodegeneration, but also in normal neural functions.

AB - Possible roles of the complement (C) system in the normal and injured brain were explored with inbred mice that carried a frameshift mutation in the C5 gene. A congenic pair was used: the C5-sufficient (C5+) B10.D2/nSnJ strain with the functional allele (Hc1) from the C57BL/10J donor strain was compared with the C5-deficient (C5-) B10.D2/oSnJ with the Hc0 allele from the C5-deficient DBA/2J donor strain. In response to the excitotoxin kainic acid (KA), C5- mice had more hippocampal pyramidal neuron death and greater induction of astrocyte mRNAs (GFAP, apoE, apoJ). In primary astrocyte cultures from unlesioned mice, an inflammatory stimulus (LPS) caused greater production of IL-6 and TNF production in C5- mice. These enhanced responses to KA and LPS suggest that hereditary C5 deficits modify responses to neurodegenerative stimuli of neurons and astrocytes. Moreover, unlesioned C5- mice had smaller input-output slopes for the NMDA component of the EPSP amplitude, but enhanced the Ca+2-dependent AMPA binding. Thus, C5 deficits also modify basal properties of glutamatergic neurotransmission that pertain to synaptic plasticity. These findings are also discussed in relation to roles of the C-system in Alzheimer disease (AD). C5 deficiencies may also be considered in the choice of strains as transgene hosts and for genetic analysis of normal and pathological brain functions. In recent transgenic studies for AD, C5- hosts showed greater neurodegeneration, consistent with the present data. These pleiotropic associations of C5 deficiency indicate roles for the C-system in neurodegeneration, but also in normal neural functions.

UR - http://www.scopus.com/inward/record.url?scp=0030175273&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030175273&partnerID=8YFLogxK

U2 - 10.1006/nbdi.1996.0020

DO - 10.1006/nbdi.1996.0020

M3 - Article

C2 - 8980020

AN - SCOPUS:0030175273

VL - 3

SP - 197

EP - 204

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

IS - 3

ER -